P694: RISK ASSESSMENT ACCORDING TO IPSS-M IS SUPERIOR TO AML ELN 2022 RISK CLASSIFICATION IN MDS/AML PATIENTS DEFINED BY ICC – IS AN INCLUSION INTO AML TRIALS JUSTIFIED?
Authors: Sandra Huber, Constance Baer, Stephan Hutter, Frank Dicker, Manja Meggendorfer, Christian Pohlkamp, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach, Gregor Hoermann
Journal: HemaSphere (2023)

Background: MDS/AML has recently been introduced as novel myeloid disease entity by the International Consensus Classification (ICC) with 10–19% blasts in the absence of AML-defining recurrent genetic abnormalities. MDS/AML is not recognized as separate entity according to the in parallel published 5th edition of the WHO classification (WHO 2022) where it largely overlaps with MDS with increased blasts 2. A main argument of the ICC to introduce the MDS/AML category was a potential eligibility of these patients for either MDS or AML clinical trials. Since predefined risk groups are commonly used as inclusion criterion for clinical trials, we asked whether AML- and/or MDS-based risk stratification was appropriate for MDS/AML patients. Aims: Evaluate prognostication in MDS/AML patients using current MDS- (Molecular International Prognostic Scoring System (IPSS-M)) and AML-based (European Leukemia Net (ELN) 2022) risk prediction systems. Methods: Non-therapy-related cases of 137 MDS/AML, 626 MDS (including 116 MDS/AML), and 686 AML patients were included. Bone marrow samples were analyzed by cytomorphology, immunophenotyping, cytogenetics, and whole genome (median coverage 100x) and transcriptome (50 Mio reads) sequencing. Results: MDS/AML patients had a median age of 74 years (female/male: 58/79). They were subclassified as MDS/AML with mutated TP53 (14%), with myelodysplasia-related (MR) gene mutations (72%) or MR cytogenetic abnormalities (4%), or not otherwise specified (10%). We first focused on the MDS-based risk prediction using the recently published IPSS-M. As expected, resulting categories for MDS/AML patients showed a clear skewing towards high risk groups (45% Very High, 29% High, 10% Moderate High, 7% Moderate Low, 9% Low and 0% Very Low) compared to a bona fide MDS cohort (14%, 12%, 7%, 11%, 41% and 15% respectively). However notably, not all MDS/AML patients were classified as very high or high risk. Importantly, we also observed a clear prognostic separation for OS of MDS/AML patients according to the different IPSS-M risk groups (p<0.001), and the OS of the respective groups was well comparable to bona fide MDS cohorts (Figure 1A). The fit of the model reflected by the concordance (c) index was similar for MDS/AML (0.7125), the total MDS cohort (0.7155) and a down-sampled sex-matched MDS cohort (0.7166). Next, we grouped our MDS/AML cohort according to AML-based risk classification using ELN 2022 guidelines. Notably, no MDS/AML patient fulfilled criteria for the favorable ELN risk group per definitionem, only 9% were classified as intermediate risk, and the vast majority (91%) as adverse risk. While within MDS/AML the intermediate risk group showed longer OS than the adverse risk group, the survival of MDS/AML patients substantially differed from a bona fide AML cohort (Figure 1B). In particular, the OS of MDS/AML patients classified as adverse risk according to ELN 2022 was significantly and clinically meaningfully longer compared to corresponding adverse risk AML patients (median OS: 1.9 vs. 0.7 years; p<0.001). Summary/Conclusion: For MDS/AML patients, MDS-based risk assessment according to IPSS-M is fully applicable despite a skewing towards high risk categories. In contrast, AML-based risk classification according to ELN 2022 guidelines is not applicable for MDS/AML. The substantially better survival of MDS/AML patients compared to adverse risk AML despite more intensive therapy in the later and higher age in the former raises concerns about a potential justification of a general inclusion of MDS/AML patients in a clinical trial designed for adverse risk AML.Keywords: ELN